The present invention relates to genetic polymorphism of MxA proteins and a method for predicting validity of interferon in an individual to be subjected to interferon therapy by using the genetic polymorphism.
Interferon is a protein secreted by vertebrate cells having antiviral activity, immunity control activity, and cell proliferation suppression activity. Therefore, interferon is widely used for treatment of various viral infectious diseases such as hepatitis C as well as malignant tumors. However, patients who do not exhibit sensitivity toward interferon have come to be known. Continuation of interferon therapy on such patients exhibiting no sensitivity to interferon therapy results in not only side effect such as fever and anemia, but also delay of initiating other treatments. Therefore, it is desirable to predict validity of interferon therapy to exclude such insensitive patients from interferon therapy, in advance.
On the other hand, an interferon-dependent protein, i.e, MxA proteins, having resistance against influenza viruses has been discovered from mice, and MxA protein has also been found in humans. In addition, it has been recently reported that expression levels of MxA mRNA and MxA proteins in patients who are infected with chronic hepatitis C virus (to be called HCV hereafter) are involved in responses of infected patients to interferon therapy. This fact suggests that MxA genes can be a useful indicator for prediction of validity of interferon therapy prior to application of the therapy.
Therefore, the present inventors examined the existence of genetic polymorphism in the MxA gene which is involved in response of HCV-infected patients to interferon therapy. The result showed that only the patients having specific genetic polymorphism of the MxA gene have sensitivity to interferon, and interferon therapy is valid to them.
In view of the circumstances mentioned above, the first object of the present invention is to provide genetic polymorphism in the promoter region of MxA gene useful in predictiong validity of interferon therapy for patients.
The second object of the present invention is to provide a method for predicting validity of interferon therapy for patients using the genetic polymorphism in the promoter region of MxA gene described above.
The third object of the present invention is to provide gene therapy and a useful vector, for rendering interferon-insensitive patients to be interferon-sensitive, using a gene of particular genetic polymorphism of the MXA genes that is responsible for interferon-sensitivity.
According to the first aspect of the present invention, there is provided a polynucleotide for predicting validity of interferon therapy, which comprises a polynucleotide selected from the group consisting of:
(at) the polynucleotide of Sequence ID No. 1 in the sequence listing;
(bt) a modified polynucleotide derived from the polynucleotide (at) by including one or several deletions, substitutions or additions at any positions except for 455th position;
(ct) a polynucleotide containing the sequence which spans from 441st to 455th position of Sequence ID No. 1;
(dt) a polynucleotide containing the sequence which spans from 449the to 459th position of Sequence ID No. 1; and
(et) a complementary strand of the polynucleotide selected from the group consisting of (at), (bt), (ct) and (dt) mentioned above.
According to the second aspect of the present invention, there is provided a polynucleotide for predicting validity of interferon therapy, which comprises a polynucleotide selected from the group consisting of:
(ag) the polynucleotide of Sequence ID No. 2 in the sequence listing;
(bg) a modified polynucleotide derived from the polynucleotide (ag) by including one or several deletions, substitutions or additions at any positions except for 455th position;
(cg) a polynucleotide containing the sequence which spans from 441st to 455th position of Sequence ID No. 2;
(dg) a polynucleotide containing the sequence which spans from 449th to 459th position of Sequence ID No. 2; and
(eg) a complementary strand of the poly nucleotide selected from the group consisting of (ag), (bg), (cg) and (dg) mentioned above.
According to the third aspect of the present invention, there is provided a polynucleotide for predicting validity of interferon therapy, which comprises a polynucleotide selected from the group consisting of:
(aa) the polynucleotide of Sequence ID No. 3 in the sequence listing;
(ba) a modified polynucleotide derived from the polynucleotide (aa) by including one or several deletions, substitutions or additions at any positions except for 455th position;
(ca) a polynucleotide containing the sequence which spans from 441st to 455th position of Sequence ID No. 3;
(da) a polynucleotide containing the sequence which spans from 449th to 459th position of Sequence ID No. 3; and
(ea) a complementary strand of the polynucleotide selected from the group consisting of (aa), (ba), (ca) and (da) mentioned above.
According to the fourth aspect of the present invention, there is provided a polynucleotide for predicting validity of interferon therapy, which comprises a polynucleotide selected from the group consisting of:
(ac) the polynucleotide of Sequence ID No. 4 in the sequence listing;
(bc) a modified polynucleotide derived from the polynucleotide (ac) by including one or several deletions, substitutions or additions at any positions except for 455th position;
(cc) a polynucleotide containing the sequence which spans from 441st to 455th position of Sequence ID No. 4;
(dc) a polynucleotide containing the sequence which spans from 449th to 459th position of Sequence ID No. 4; and
(ec) a complementary strand of the polynucleotide selected from the group consisting of (ac), (bc), (cc) and (dc) mentioned above.
According to the fifth aspect of the present invention, there is provided a method of predicting whether interferon therapy is valid or not for an individual requiring interferon administration, comprising the steps of
1) taking a sample containing a polynucleotide which includes at least one interferon-stimulated response element from the individual; and
2) determining nucleotide located at the 2nd position from the 3xe2x80x2 end of the at least one interferon-stimulated response element.
In the method, it can be predicted that interferon therapy is valid for the individual when the nucleotide is thymine. On the other hand, when the nucleotide is guanine, adenine, or cytosine, it can be predicted that interferon therapy is highly possibly invalid for the individual.
According to the sixth aspect of the present invention, there is provided a test reagent for predicting whether interferon therapy is valid or not for an individual requiring interferon therapy, which comprises a polynucleotide selected from the group consisting of (at) to (et), (ag) to (eg), (aa) to (ea), and (ac) to (ea) described above.
According to the seventh aspect of the present invention, there is provided a probe for detecting polymorphism existing in a promoter region of MxA gene, comprising a polynucleotide selected from the group consisting of (at) to (et), (ag) to (eg), (aa) to (ea), and (ac) to (ea) described above.
According to the eighth aspect of the present invention, there is provided use of the a polynucleotide selected from the group consisting of (at) to (et), (ag) to (eg), (aa) to (ea), and (ac) to (ea) described above, for predicting validity of interferon.
According to the ninth aspect of the present invention, there is provided a vector for rendering an interferon-insensitive individual to be interferon-sensitive, which contains at least one polynucleotide selected from the group consisting of the polynucleotides (at), (bt), (ct), (dt) and (et) described above.
According to the tenth aspect of the present invention, there is provided a method for rendering an interferon-insensitive individual to be interferon-sensitive, which comprises introducing a polynucleotide containing at least one polynucleotide selected from the group consisting of the polynucleotides (at), (bt), (ct), (dt) and (et) described above into the interferon-insensitive individual.
According to the eleventh aspect of the present invention, there is provided use of a polynucleotide which contains at least one polynucleotide selected from the group consisting of the polynucleotides (at), (bt), (ct), (dt) and (et) described above, in the production of pharmaceuticals for rendering an interferon-insensitive individual to be interferon-sensitive.
According to the twelfth aspect of the present invention, there is provided a non-human transgenic animal, which has been introduced with a polynucleotide which contains at least one polynucleotide selected from the group consisting of the polynucleotides (at), (bt), (ct), (dt) and (et) described above.